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Non-communicable diseases (NCD) such as cancer, heart disease and cerebrovascular injury are dependent on or aggravated by inflammation. Their prevention and treatment is arguably one of the greatest challenges to medicine in the 21st century. The pleiotropic, proinflammatory cytokine; interleukin-l beta (IL-l~) is a primary, causative messenger of inflammation. Lipopolysaccharide (LPS) induction ofIL-l~ expression via toll-like receptor 4 (TLR4) in myeloid cells is a robust experimental model of inflammation and is driven in large part via p38-MAPK and NF-KB signaling networks. The control of signaling networks involved in IL-l~ expression is distributed and highly complex, so to perturb intracellular networks effectively it is often necessary to modulate several steps simultaneously. However, the number of possible permutations for intervention leads to a combinatorial explosion in the experiments that would have to be performed in a complete analysis. We used a multi-objective evolutionary algorithm (EA) to optimise reagent combinations from a dynamic chemical library of 33 compounds with established or predicted targets in the regulatory network controlling IL-l ~ expression. The EA converged on excellent solutions within 11 generations during which we studied just 550 combinations out of the potential search space of - 9 billion. The top five reagents with the greatest contribution to combinatorial effects throughout the EA were then optimised pair- wise with respect to their concentrations, using an adaptive, dose matrix search protocol. A p38a MAPK inhibitor (30 ± 10% inhibition alone) with either an inhibitor of IKB kinase (12 ± 9 % inhibition alone) or a chelator of poorly liganded iron (19 ± 8 % inhibition alone) yielded synergistic inhibition (59 ± 5 % and 59 ± 4 % respectively, n=7, p≥O.04 for both combinations, tested by one way ANOVA with Tukey's multiple test correction) of macrophage IL-l~ expression. Utilising the above data, in conjunction with the literature, an LPS-directed transcriptional map of IL-l ~ expression was constructed. Transcription factors (TF) targeted by the signaling networks coalesce at precise nucleotide binding elements within the IL-l~ regulatory DNA. Constitutive binding of PU.l and C/EBr-~ TF's are obligate for IL-l~ expression. The findings in this thesis suggest that PU.l and C/EBP-~ TF's form scaffolds facilitating dynamic control exerted by other TF's, as exemplified by c-Jun. Similarly, evidence is emerging that epigenetic factors, such as the hetero-euchromatin balance, are also important in the relative transcriptional efficacy in different cell types. Evolutionary searches provide a powerful and general approach to the discovery of novel combinations of pharmacological agents with potentially greater therapeutic indices than those of single drugs. Similarly, construction of signaling network maps aid the elucidation of pharmacological mechanism and are mandatory precursors to the development of dynamic models. The symbiosis of both approaches has provided further insight into the mechanisms responsible for IL-lβ expression, and reported here provide a - platform for further developments in understanding NCD's dependent on or aggravated by inflammation.

Rough set theory (RST) is concerned with the formal approximation of crisp sets and is a mathematical tool which deals with vagueness and uncertainty. RST can be integrated into machine learning and can be used to forecast predictions as well as to determine the causal interpretations for a particular data set. The work performed in this research is concerned with using various optimisation techniques to granulise the rough set input partitions in order to achieve the highest forecasting accuracy produced by the rough set. The forecasting accuracy is measured by using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. The four optimisation techniques used are genetic algorithm, particle swarm optimisation, hill climbing and simulated annealing. This newly proposed method is tested on two data sets, namely, the human immunodeficiency virus (HIV) data set and the militarised interstate dispute (MID) data set. The results obtained from this granulisation method are compared to two previous static granulisation methods, namely, equal-width-bin and equal-frequency-bin partitioning. The results conclude that all of the proposed optimised methods produce higher forecasting accuracies than that of the two static methods. In the case of the HIV data set, the hill climbing approach produced the highest accuracy, an accuracy of 69.02% is achieved in a time of 12624 minutes. For the MID data, the genetic algorithm approach produced the highest accuracy. The accuracy achieved is 95.82% in a time of 420 minutes. The rules generated from the rough set are linguistic and easy-to-interpret, but this does come at the expense of the accuracy lost in the discretisation process where the granularity of the variables are decreased.

Short Term Conflict Alert (STCA) is an automated warning system designed to alert air traffic controllers to possible loss of separation between aircraft. STCA systems are complex, with many parameters that must be adjusted to achieve best performance. Current procedure is to manually ‘tune’ the governing parameters in order to finely balance the trade-off between wanted alerts and nuisance alerts. We present an incremental approach to automatically optimising STCA systems, using a simple evolutionary algorithm. By dividing the parameter space into regional subsets, we investigate methods of reducing the number of evaluations required to generate the Pareto optimal Receiver Operating Characteristic (ROC) curve. Multi-archive techniques are devised and are shown to cut the necessary number of iterations by half. A method of estimating the fitness of recombined regional parameter subsets without actual evaluation on the STCA system is presented, however, convergence is shown to be severely stunted when relatively weak sources of noise are present. We describe a method of aggressively perturbing parameters outside of their known ‘safe’ ranges when complex inhibitory interactions are present that prevent an exhaustive search of permitted values. The scheme prevents the optimiser from repeating ‘mistakes’ and unnecessarily wasting evaluations. Results show that a more complete picture of the Pareto-optimal ROC curve may be obtained without increasing the number of necessary iterations. Efficacy of the new methods is discussed, with suggestions for improving efficiency. Sources of parameter interdependence and noise are explored and where possible mitigating techniques and procedures suggested. Classifier performance on training and test data is investigated and potential solutions for reducing overfitting are evaluated on a toy problem. We comment on potential uses of the ROC in characterising STCA performance, for comparison to other systems and airspaces. Many industrial systems are structured in a similar way to STCA, we hope that techniques presented will be applicable to other highly parametrised, expensive problem domains.

In der vorliegenden Arbeit werden zwei Modelle zur strukturellen Analyse von Stoffwechselsystemen vorgestellt. Die Untersuchung basiert auf der Hypothese, dass heutzutage vorzufindende Stoffwechselsysteme als Ergebnis einer evolutionären Entwicklung, bestimmt durch Mutationsmechanismen und natürlicher Selektion, angesehen werden können. Es kann daher angenommen werden, dass kinetische Parameter sowie strukturelle Eigenschaften im Laufe der Evolution solche Werte angenommen haben, die eine gewisse Optimalität bezüglich ihrer biologischen Funktion darstellen. Das erste Modell untersucht das strukturelle Design ATP und NADH produzierender Systeme, so wie die Glykolyse und der Zitratzyklus. Eine Methode wird präsentiert, die die Beschreibung hypothetischer, chemisch denkbarer, alternativer Stoffwechselwege ermöglicht. Diese Wege werden bezüglich ihrer Effizienz, ATP zu produzieren, untersucht. Es stellt sich heraus, dass die meisten möglichen Wege eine niedrige ATP-Produktionsrate aufweisen und dass die effizientesten Wege einige strukturelle Gemeinsamkeiten besitzen. Die Optimierung bezüglich der ATP-Produktionsrate wird mit einem evolutionären Algorithmus durchgeführt. Folgende Resultate stehen mit dem tatsächlichen Design der Glykolyse und des Zitratzyklus in Einklang: (i) In allen effizienten Wegen befinden sich die ATP-verbrauchenden Reaktionen am Anfang. (ii) In allen effizienten Wegen befinden sich die sowohl die NADH- als auch die ATP-produzierenden Reaktionen am Ende. (iii) Die Anzahl der NADH-Moleküle, die aus einem energiereichen Molekül (Glukose) produziert werden, beläuft sich in allen effizienten Wegen auf vier. Im zweiten Modell werden vollständige Mengen metabolischer Netzwerke konstruiert, wobei von Reaktionen ausgegangen wird, die Änderungen des Kohlenstoffskeletts der beteiligten Metabolite beschreiben. Elementare Netzwerke werden dadurch definiert, dass eine bestimmte chemische Umwandlung durchgeführt werden kann und dass diese Fähigkeit verloren geht, wenn eine der beteiligten Reaktionen ausgeschlossen wird. Übergänge zwischen Netzwerken und Mutationen werden durch den Austausch einer einzigen Reaktion definiert. Es existieren verschiedene Mutationen, solche bei denen Funktionen verloren gehen, welche dazugewonnen werden, und neutrale Mutationen. Mutationen definieren Nachbarschaftsrelationen, die graphentheoretisch beschrieben werden. Eigenschaften wie Durchmesser, Konnektivität und die Abstandsverteilung der Vertizes werden berechnet. Ein Konzept zur Quantifizierung der Robustheit von Netzwerken gegenüber stöchiometrischen Veränderungen wird entwickelt, wobei zwischen starker und schwacher Robustheit unterschieden wird. Evolutionäre Algorithmen werden angewandt, um die Entwicklung von Netzwerkpopulationen unter konstanten und zeitlich veränderlichen Umweltbedingungen zu untersuchen. Es wird gezeigt, dass Populationen sich zu Gruppierungen von Netzwerken hinentwickeln, die gemeinsame Funktionen besitzen und nah benachbart sind. Unter zeitlich veränderlichen Umweltbedingungen zeigt sich, dass multifunktionelle Netzwerke optimal sind und sich im Selektionsprozess durchsetzen. / In the present thesis two models are presented which study the structural design of metabolic systems. The investigation is based on the hypothesis that present day metabolic systems are the result of an evolutionary development governed by mutation mechanisms and natural selection principles. Therefore, it can be assumed that these parameters have reached, during the course of their evolution, values which imply certain optimal properties with respect to their biological function. The first model concerns the structural design of ATP and NADH producing systems such as glycolysis and the citric acid cycle. A method is presented to describe hypothetical, chemically feasible, alternative pathways. We analyse these pathways with respect to their capability to efficiently produce ATP. It is shown that most of the possible pathways result in a very low ATP production rate and that the very efficient pathways share common structural properties. Optimisation with respect to the ATP production rate is performed by an evolutionary algorithm. The following results of our analysis are in close correspondence to the real design of glycolysis and the TCA cycle: (i) In all efficient pathways the ATP consuming reactions are located near the beginning. (ii) In all efficient pathways NADH producing reactions as well as ATP producing reactions are located near the end. (iii) The number of NADH molecules produced by the consumption of one energy-rich molecule (glucose) amounts to four in all efficient pathways. In the second model complete sets of metabolic networks are constructed starting from a limited set of reactions describing changes in the carbon skeleton of biochemical compounds. Elementary networks are defined by the condition that a specific chemical conversion can be performed by a set of given reactions and that this ability will be lost by elimination of any of these reactions. Transitions between networks and mutations of networks are defined by exchanges of single reactions. Different mutations exist such as gain or loss of function mutations and neutral mutations. Based on these mutations neighbourhood relations between networks are established which are described in a graph theoretical way. Basic properties of these graphs are determined such as diameter, connectedness, distance distribution of pairs of vertices. A concept is developed to quantify the robustness of networks against changes in their stoichiometry where we distinguish between strong and weak robustness. Evolutionary algorithms are applied to study the development of network populations under constant and time dependent environmental conditions. It is shown that the populations evolve toward clusters of networks performing a common function and which are closely neighboured. Under changing environmental conditions multifunctional networks prove to be optimal and will be selected.

This thesis describes the addition of novel Geometric Guides to a generative Computer-Aided Design (CAD) application that supports early-stage concept generation. The application generates and evolves abstract 3D shapes, used to inspire the form of new product concepts. It was previously a conventional Interactive Evolutionary system where users selected shapes from evolving populations. However, design industry users wanted more control over the shapes, for example by allowing the system to influence the proportions of evolving forms. The solution researched, developed, integrated and tested is a more cooperative human-machine system combining classic user interaction with innovative geometric analysis. In the literature review, different types of Interactive Evolutionary Computation (IEC), Pose Normalisation (PN), Shape Comparison, and Minimum-Volume Bounding Box approaches are compared, with some of these technologies identified as applicable for this research. Using its Application Programming Interface, add-ins for the Siemens NX CAD system have been developed and integrated with an existing Interactive Evolutionary CAD system. These add-ins allow users to create a Geometric Guide (GG) at the start of a shape exploration session. Before evolving shapes can be compared with the GG, they must be aligned and scaled (known as Pose Normalisation in the literature). Computationally-efficient PN has been achieved using geometric functions such as Bounding Box for translation and scaling, and Principle Axes for the orientation. A shape comparison algorithm has been developed that is based on the principle of non-intersecting volumes. This algorithm is also implemented with standard, readily available geometric functions, is conceptually simple, accessible to other researchers and also offers appropriate efficacy. Objective geometric testing showed that the PN and Shape Comparison methods developed are suitable for this guiding application and can be efficiently adapted to enhance an Interactive Evolutionary Design system. System performance with different population sizes was examined to indicate how best to use the new guiding capabilities to assist users in evolutionary shape searching. This was backed up by participant testing research into two user interaction strategies. A Large Background Population (LBP) approach where the GG is used to select a sub-set of shapes to show to the user was shown to be the most effective. The inclusion of Geometric Guides has taken the research from the existing aesthetic focused tool to a system capable of application to a wider range of engineering design problems. This system supports earlier design processes and ideation in conceptual design and allows a designer to experiment with ideas freely to interactively explore populations of evolving solutions. The design approach has been further improved, and expanded beyond the previous quite limited scope of form exploration.

Battery powered wireless sensors are widely used in industrial and regulatory monitoring applications. This is primarily due to the ease of installation and the ability to monitor areas that are difficult to access. Additionally, they can be left unattended for long periods of time. However, there are many challenges to successful deployments of wireless sensor networks (WSNs). In this thesis we draw attention to two major challenges. Firstly, with a view to extending network range, modern WSNs use mesh network topologies, where data is sent either directly or by relaying data from node-to-node en route to the central base station. The additional load of relaying other nodes’ data is expensive in terms of energy consumption, and depending on the routes taken some nodes may be heavily loaded. Hence, it is crucial to locate routes that achieve energy efficiency in the network and extend the time before the first node exhausts its battery, thus improving the network lifetime. Secondly, WSNs operate in a dynamic radio environment. With changing conditions, such as modified buildings or the passage of people, links may fail and data will be lost as a consequence. Therefore in addition to finding energy efficient routes, it is important to locate combinations of routes that are robust to the failure of radio links. Dealing with these challenges presents a routing optimisation problem with multiple objectives: find good routes to ensure energy efficiency, extend network lifetime and improve robustness. This is however an NP-hard problem, and thus polynomial time algorithms to solve this problem are unavailable. Therefore we propose hybrid evolutionary approaches to approximate the optimal trade-offs between these objectives. In our approach, we use novel search space pruning methods for network graphs, based on k-shortest paths, partially and edge disjoint paths, and graph reduction to combat the combinatorial explosion in search space size and consequently conduct rapid optimisation. The proposed methods can successfully approximate optimal Pareto fronts. The estimated fronts contain a wide range of robust and energy efficient routes. The fronts typically also include solutions with a network lifetime close to the optimal lifetime if the number of routes per nodes were unconstrained. These methods are demonstrated in a real network deployed at the Victoria & Albert Museum, London, UK.

The aim of this work was to create a system for optimisaton of specific analog circuits by evolution using multiple fitness functions . A set of experiments was run, and the results analyzed to evaluate the feasibility of evolutionary optimisation of analog circuits . A requirement for this goal is the study and choice of certain types of analog circuits and evolutionary algorithms . For the scope of this work , amplifiers and oscillators were chosen as target circuits , and genetic algorithms and evolutionary strategies as evolutionary algorithms . The motivation for this work is the ongoing effort to automate the design and optimisation of analog circuits , where evolutionary optimisation is one of the options .